title: [Personalized drug therapy-directed clinical pharmacology research based on genetic polymorphisms and pharmacokinetics analysis].
abstract: In this decade, the field of pharmacogenomics (PGx), which is related to pharmacokinetics (PK) or pharmacodynamics (PD), has attracted much attention because it may provide a possible explanation for individual differences in the clinical efficacy of drugs. For the development of personalized drug therapy, it is important to accumulate evidence from PK/PD/PGx analysis in clinical trials. Warfarin (WF) is one of the most widely prescribed anticoagulants for the prevention and treatment of venous and arterial thromboembolism. However, large interindividual and interethnic differences have been observed in the WF dose required to elicit the anticoagulant effect. We investigated the factors influencing the WF maintenance dose in Japanese patients. Our study confirmed a large interindividual variability in the WF maintenance dose that was due to a VKORC1 1639 G>A polymorphism and differences in body weight, age, and serum albumin. In addition, we found that the CYP4F2 genotype affects the plasma concentration of menaquinone-4, and that this finding was correlated with the WF sensitivity index in Japanese pediatric patients. Methotrexate (MTX) is an antifolate that is widely used to treat rheumatoid arthritis (RA) and cancer. The response to low-dose MTX demonstrated wide interpatient variability; however, the contributing factors remain unclear. We found that the frequency of the RFC1 80A allele was higher in RA patients treated with MTX alone compared with patients who received biological disease-modifying antirheumatic drugs (bDMARDs). This finding may support the combined use of bDMARDs and MTX. Further large-scale prospective clinical trials are required to confirm these findings.
authors.affiliation: Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayashi
mesh_terms: D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics; D044466:Asian People; D002986:Clinical Trials as Topic; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D004359:Drug Therapy, Combination; D005787:Gene Frequency / Q000235:genetics; D006801:Humans; D060046:Maintenance Chemotherapy; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics; D010599:Pharmacokinetics; D011110:Polymorphism, Genetic; D057285:Precision Medicine / Q000379:methods* / Q000639:trends; D051818:Replication Protein C / Q000235:genetics; D013923:Thromboembolism / Q000188:drug therapy / Q000517:prevention & control; D024482:Vitamin K 2 / Q000031:analogs & derivatives / Q000097:blood; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D018501:Antirheumatic Agents; C081632:RFC1 protein, human; D024482:Vitamin K 2; C030814:menatetrenone; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D051818:Replication Protein C; D008727:Methotrexate